Date of Award

Spring 1-1-2011

Document Type


Degree Name

Doctor of Philosophy (PhD)


Psychology & Neuroscience

First Advisor

Linda Watkins

Second Advisor

Steven Maier

Third Advisor

Mark R Hutchinson


Toll-like receptor 4 (TLR4) has recently been implicated in both chronic neuropathic pain and in counter-regulating morphine analgesia. The studies undertaken here further show the potential for TLR4 signaling activation to produce pain states. Specifically, a group of metabolites, glucuronide metabolites, are shown to activate TLR4 signaling in an in vitro model and cause transient acute pain when injected intrathecally in small doses. The glucuronide metabolites tested included morphine-3-glucuronide, ethyl glucuronide, corticosterone-21-glucuronide, estradiol-3-glucuronide, and estradiol-17-glucuronide, as well as glucuronic acid itself. These metabolites were previously considered largely non-reactive without known biological activity or toxicity at clinically relevant doses. The current studies present the first evidence that they may cause TLR4- dependent enhanced pain, which could have influence in diverse conditions such as morphine withdrawal hyperalgesia, hangover headache and menstrual migraine. Additionally, a TLR4 signaling inhibitor, (+)-naloxone was tested in neuropathic pain and morphine-3-glucuronide induced pain. (+)-Naloxone does not act on opioid receptors, as the (-)-naloxone isomer does, but has been shown to reduce TLR4 signaling in vitro and in vivo. (+)-Naloxone blocked the development of pain following intrathecal morphine-3- glucuronide injection, and reversed neuropathic pain in multiple models, up to 4 months following nerve injury. (+)-Naloxone is a candidate small molecule, blood-brain barrier permeable molecule for treating pain conditions where TLR4 is involved.